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“Changing to an alternative chemotherapy after one cycle of chemotherapy does not improve overall survival or progression-free survival for patients with metastatic breast cancer whose circulating tumor cells don't decrease to less than five after a single cycle of chemotherapy,” Jeffrey B. Smerage, MD, PhD, Clinical Associate Professor of Medical Oncology at the University of Michigan Comprehensive Cancer Center, said at a news briefing.

Among the 64 women maintained on their original regimen, 50 deaths were recorded after 12 months; among the 59 women who were switched to an alternate regimen, there were 48 deaths after 12 months.

“As you can see, there is no difference in median overall survival or in overall survival in general between these two randomized arms,” he said. “Similarly, no statistically significant difference was seen in progression-free survival. The median progression-free survival in those women who maintained their regimen was 3.5 months while in the group of women where the therapy was changed, it was 4.6 months.” That represented a reduction in risk of progression of about nine percent.

He said, though, that while the idea that circulating tumor cell counts could help guide therapy failed, use of the cells is far from over: “This study was based on counting the number of CTCs in blood. Several groups are now investigating the presence of biological markers such as estrogen receptor and HER2 on circulating tumor cells. It is hoped that the measurement of these markers may allow for better prediction of what therapies will work best for these patients.”

At the time this trial, SWOG SO500, was initiated, technology only allowed for counting of circulating tumor cells, but now the cells can be assessed for other biomarkers, which might make it possible to be more selective, he said. “For example, the use of the cells could help determine who might benefit from hormonal therapies. I'm optimistic that these smaller studies will be positive so we can more on with larger studies.”

Important Comparison

“What is probably the most important result of this clinical trial,” he continued, “is the comparison of those three arms: The women who had low circulating tumor cells at the beginning of the trial before having chemotherapy; the second arm of those patients who converted to low circulating tumor cells after the first round of chemotherapy, and then the combined randomized arms of patients who remained with high circulating tumor cells after one treatment cycle.”

Among the 276 women who had fewer than five circulating tumor cells at baseline, there were 146 deaths, for a median overall survival of 35 months; among the 163 women who had fewer than five CTCs after the first round of chemotherapy, there were 107 deaths, for a median overall survival of 23 months; and among the 123 women who had five or more CTCs after the first round of chemotherapy—those were in the trial to determine if changing chemotherapy regimens made any difference in outcomes—there were 98 deaths, for a median overall survival of 13 months.

Approximately 25 percent of the women who had low levels of CTCs at baseline were still alive five years after initiating therapy. Among women with elevated CTCs, 75 percent had died within 18 months of initiating therapy.

“These are disappointing data based on the hope that a change in circulating tumor cell number could help guide therapy,” commented Edith Perez, MD, Professor of Medicine and Deputy Director at Large at the Mayo Clinic Cancer Center in Jacksonville, Fla.

“So, for now the circulating tumor cell number is prognostic—adding to the list of many other prognostics, including performance status, prior therapy, presence of visceral disease, and in the setting of HER2-positive breast cancer, we could add increased soluble human epidermal growth factor receptor 2 (sHER2) and PI3K mutations,” she said.

Still, said Smerage, “it is important to note that this study was not designed to detect the benefits of chemotherapy, so it would not be a correct assumption to say that these patients derived no benefit from chemotherapy.

“The population of patients whose circulating tumor cells don't fall to less than five after one cycle of chemotherapy are clearly at higher risk, and that might influence treatment choices, including the participation in clinical and translational studies of novel and maybe targeted therapies.”

He said the study results might influence doctors and patients into entering clinical trials at an earlier point rather than staying with more of the standard currently approved drugs.

The researchers conceived the SO500 trial in the belief that women with elevated CTCs after undergoing one round of chemotherapy might be on ineffective treatment, Smerage explained, noting that CTCs can be detected in the peripheral vascular system and are observed in a variety of cancers, not just breast cancer.

“For this study we used the CellSearch System, which is the only FDA-cleared platform for circulating tumor cells, cleared for determining prognosis and for monitoring breast cancer therapy.”

In the study—which was funded by the National Cancer Institute, and in part by Veridex, which makes the Cell Search System—the researchers focused on women whose blood samples were drawn at their first follow-up after having started chemotherapy.

“The patients come back for their next visit, and they get another blood sample drawn. For those patients who have elevated cells at first follow-up, the time to clinical progression would be approximately one month compared with seven months for those who low levels—i.e., less than five circulating tumor cells,” he said.

“The concept was that we could identify these patients early, switch them to an alternative therapy with the idea that they would benefit from that early switch and in that way they would avoid unnecessary chemotoxicity from a therapy that is presumably not working and also would potentially allow them to switch to another therapy that might improve the odds that they would be on an effective therapy.”

The researcher enrolled 595 women into the study between 2006 and 2012. CTCs were enumerated at baseline prior to the first line of chemotherapy. In the trial, 276 women had fewer than five CTCs, and these women were monitored for progression-free and overall survival.

If the women had five or more CTCs at baseline, they then underwent chemotherapy. Three weeks after the first dose of chemotherapy, the patients were then re-assessed for circulating tumor cells.

Those 123 women with five or more CTCs after the first round of chemotherapy were randomly assigned to two treatment strategies, testing overall survival as a primary endpoint. This was the group analyzed to determine if guiding therapy on the basis of CTCs was a beneficial strategy.

iPad Extra!

In a video interview on the iPad edition of this issue with OT reporter Dan Keller, Dr. Smerage elaborates on the clinical results of the trial, noting that researchers had hoped that changing regimens could provide a more effective therapy and spare patients from needless toxicities. After the disappointing results, however, he said that it is clear that this population needs more effective treatment options beyond traditional chemotherapies.

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